Postoperative Prognostic Nutritional Index and Fibrinogen Could Well Predict Poor Prognosis of Acute Type A Aortic Dissection Patients After Surgery

Introduction Inflammatory and immunological factors play pivotal roles in the prognosis of acute type A aortic dissection. We aimed to evaluate the prognostic values of immune-inflammatory parameters in acute type A aortic dissection patients after surgery. Methods A total of 127 acute type A aortic dissection patients were included. Perioperative clinical data were collected through the hospital’s information system. The outcomes studied were delayed extubation, reintubation, and 30-day mortality. Multivariate logistic regression analysis and receiver operating characteristic analysis were used to screen the risk factors of poor prognosis. Results Of all participants, 94 were male, and mean age was 51.95±11.89 years. The postoperative prognostic nutritional indexes were lower in delayed extubation patients, reintubation patients, and patients who died within 30 days. After multivariate regression analysis, the postoperative prognostic nutritional index was a protective parameter of poor prognosis. The odds ratios (95% confidence interval) of postoperative prognostic nutritional index were 0.898 (0.815, 0.989) for delayed extubation and 0.792 (0.696, 0.901) for 30-day mortality. Low postoperative fibrinogen could also well predict poor clinical outcomes. The odds ratios (95% confidence interval) of postoperative fibrinogen were 0.487 (0.291, 0.813) for delayed extubation, 0.292 (0.124, 0.687) for reintubation, and 0.249 (0.093, 0.669) for 30-day mortality. Conclusion Postoperative prognostic nutritional index and postoperative fibrinogen could be two promising markers to identify poor prognosis of acute type A aortic dissection patients after surgery.


INTRODUCTION
Acute type A aortic dissection (ATAAD) is a life-threatening cardiovascular emergency, which accounts for 58-62% of all aortic dissection (AD) with extremely high mortality and disability rates [1] .According to data from the International Registry of Acute Aortic Dissection, in-hospital surgical mortality rate could be as high as 30%, and the mortality rates after discharge range from 4-48% at the 1 st year and 9-63% at the 5 th year [2] .Therefore, it is important to accurately identify high-risk ATAAD patients by exploring the predictors of poor prognosis.
Accumulating evidence has confirmed that inflammatory and immunological factors are intimately involved in the progression and prognosis of ATAAD [3,4] .Inflammatory cell infiltration contributes to a sustained injury response, leading to medial degeneration and AD formation [4] .Several inflammatory factors, such as C-reactive protein, interleukin-6, tumor necrosis factor-α, and pentraxin-3, are increased in ATAAD patients [5] .The JAK2 gene, which is involved in the regulation of inflammatory response, was significantly downregulated in aortic specimens of ATAAD patients [6] .Anti-inflammatory liposome therapy alleviates aortic injury and prolongs survival time in both acute and chronic AD mice [7] .An Italian study found that T lymphocytes were reduced in the thoracic aortic specimens and peripheral blood of ATAAD patients [5] .Innate and cytotoxic cells are upregulated and are involved in the pathogenesis of ATAAD.Due to this association, multiple systemic inflammatory and immune biomarkers have been studied in AD to predict its prognosis, including neutrophil-lymphocyte ratio (NLR), systemic immune-inflammation index (SII), and prognostic nutritional index (PNI).Higher NLR and SII were associated with adverse events in the hospital or during follow-up in AD patients [8,9] .Patients with a lower preoperative PNI showed significantly higher in-hospital mortality, a higher proportion of prolonged mechanical ventilation (MV), and longer intensive care unit (ICU) stay after surgery for ATAAD [10,11] .In addition, several new biomarkers derived from NLR were correlated with systemic inflammation and immune status and were good prognostic indicators of malignant tumors and cardiovascular diseases, including systemic inflammation response index (SIRI), advanced lung cancer inflammation index (ALI), and pan-immuneinflammation value (PIV) [12,13] .These indices outperformed other well-known peripheral blood parameters.However, it remains to be clarified whether these indices can act as prognostic biomarkers of ATAAD, and which one is optimal.Therefore, the present study explored the predictive value of SIRI, SII, ALI, PNI, and PIV on delayed extubation, reintubation, and 30-day mortality.We further compared the sensitivity and specificity of these indices in the prediction of adverse outcomes.We aimed to identify the optimal indicator to guide risk stratification and treatment of ATAAD patients.

Study Subjects
Patients diagnosed with ATAAD from September 2020 to September 2021 were enrolled in this study.The diagnosis of ATAAD was confirmed by computed tomographic angiography.
Patients who underwent no surgical treatment or who died during the operation were excluded.There were 142 ATAAD patients at first.Of these patients, seven were excluded because they did not receive surgical therapy due to aortic rupture or economic factors or died during the operation, three were excluded because some clinical data were missing, and another five patients who were lost to follow-up at the 1 st month after surgery were also excluded (Figure 1).The study was conducted in accordance with the Declaration of Helsinki and was approved by the Medical Science Research Ethics Committee of the First Affiliated Hospital of Xi'an Jiaotong University (No.2021-621), and individual consent for this retrospective analysis was waived.

Data Collection and Definition
Perioperative clinical data of all patients, including demographic characteristics, laboratory parameters, surgical information, and detailed data of MV and reintubation, were retrospectively collected through the hospital's information system.The prognostic indices included delayed extubation, reintubation, and 30-day mortality.Delayed extubation was defined as MV for > 48 hours.Patients were followed up at the 1 st month after surgery through re-examination in the outpatient clinic or telephone consultation.Body mass index (BMI) was calculated as weight/height2 (kg/m2).The immune-inflammation parameters were obtained according to the following formulas:

Surgical Technique
The operation was performed by a surgical team with the patient under general anesthesia.Cardiopulmonary bypass (CPB) was established at different sites according to the status of the patient (right axillary artery, femoral artery, innominate artery, and double arterial cannulation).Left radial artery and left dorsalis pedis artery catheterization for pressure measurement were performed.The patient was cooled to 28°C (nasopharyngeal temperature).The ascending aorta was clamped, and cold blood cardioplegia was infused through the coronary ostia to accomplish cardiac arrest.Antegrade cerebral perfusion for brain protection was established by axillary perfusion with a clamped brachiocephalic artery and direct cannulation of the left common carotid and subclavian arteries.The detailed operation procedure depended on the specific pathological changes of each patient, including Bentall procedure, David procedure, ascending aorta replacement + semiarch or total arch replacement, or Sun's procedure (total arch replacement using a tetrafurcate graft with stented elephant trunk implantation).Some patients also concomitantly underwent coronary artery bypass grafting (CABG) and ascending-femoral bypass.
Brazilian Journal of Cardiovascular Surgery

Baseline Characteristics of Participants by Clinical Outcomes
A total of 127 patients were included in this study.Ninety-four of them were male, and the mean age was 51.95±11.89years.A total of 49.6% were hypertensive.The rates of delayed extubation, reintubation, and 30-day mortality were 43.7%, 16.8%, and 13.6%, respectively, in the present study.Eighty-six patients underwent ascending aorta replacement + Sun's procedure, 24 underwent Bentall procedure + Sun's procedure, six underwent David procedure + Sun's procedure, five underwent Bentall procedure, three underwent Bentall procedure + semiarch replacement, two underwent ascending aorta + semiarch replacement, and one underwent ascending aorta replacement.In addition, seven patients underwent ascending-femoral bypass, and two underwent CABG.Eight patients who died or were discharged within 48 hours after surgery for personal reasons were excluded from the analysis of delayed extubation.Fourteen patients Brazilian Journal of Cardiovascular Surgery who had never been weaned from MV were excluded from the reintubation analysis.
The groups with different clinical outcomes (Table 1) had comparable baseline characteristics, except for a higher malperfusion rate in the delayed extubation group.Surgery time was longer in reintubated patients and patients who died within 30 days.The rate of ascending-femoral bypass was higher in patients who died within 30 days.Delayed extubation patients had a longer CPB time and a higher rate of David procedure.D-dimer and fibrinogen (FIB) degradation products at admission were significantly higher in patients who died within 30 days but lower in delayed extubation patients.We also found that postoperative FIB (postFIB) was significantly lower in delayed extubation patients, reintubation patients, and patients who died within 30 days (P-values 0.001, 0.001, and 0.003, respectively).Among all immune-inflammatory parameters (Table 2), preoperative SIRI and PIV were higher and PNI was lower in delayed extubation patients.The postoperative PNIs (postPNI) were significantly lower in longer MV patients, reintubation patients, and patients who died within 30 days (P-values 0.003, 0.027, and 0.009, respectively).Pre and postoperative ALI did not show significant differences between groups.These results indicated that postFIB and postPNI were intimately correlated with poor clinical outcomes.

Risk Factors for Poor Clinical Outcomes
By multivariate logistic regression analysis adjusted for age, sex, BMI, history of diseases, smoking, drinking, and preoperative malperfusion, postPNI and postFIB were the two protective parameters of poor clinical outcomes.The odds ratios (ORs) (95% confidence interval [CI]) of postPNI were 0.898 (0.815, 0.989) for delayed extubation and 0.792 (0.696, 0.901) for 30-day mortality.

Discriminating Performances of PostPNI and PostFIB in Predicting Poor Clinical Outcomes
To determine the prognostic predictive abilities of postPNI and postFIB for a poor clinical prognosis of ATAAD after surgery, we conducted ROC analysis.The areas under the curve (AUCs) for postPNI were 0.659 (

DISCUSSION
This study explored the prognostic predictive and discriminative abilities of different immune-inflammatory parameters, including SIRI, SII, PNI, ALI, and PIV, in ATAAD patients after surgery.The prognostic indices included delayed extubation, reintubation, and 30-day mortality.The rates of delayed extubation, reintubation, and 30-day mortality were 43.7%, 16.8%, and 13.6%, respectively.The 30-day mortality was similar to those in previous multicenter studies, which uniformly approximately 17%.We found that only low postPNI was intimately associated with delayed extubation and 30-day mortality.Other perioperative immune-inflammatory indices did not present any predictive value of poor clinical outcomes after ATAAD surgery.In addition, low postFIB could well predict poor clinical outcomes.Aberrant activation of the immune-inflammatory system plays a pivotal role in the progression of AD, contributing to vascular remodeling and dissection formation [14] .In ATAAD patients, neutrophils usually secrete cytokines in response to inflammatory stimuli, and cellular immunity is weakened, which is indicated by a decrease in lymphocytes.Therefore, NLR and NLR-derived parameters could reflect the general immune-inflammatory status.In this study, preNLR and postNLR were 14.93±14.57and 27.06±19.13,respectively, indicating the activation of inflammation.
Studies have reported that NLR can distinguish AD from other acute chest pain diseases, and patients with a higher NLR tend to have higher in-hospital mortality [8,15] .There are few data on the relationship of SIRI, SII, ALI, and PIV with the prognosis of ATAAD after surgery.
In this study, we did not find any significant differences between different groups divided by delayed extubation, reintubation, or 30-day mortality.
Previous studies have proposed albumin as an indicator of protein status in non-inflamed patients, but it is not nutritionally informative in an ICU setting.The distribution between the intravascular and extravascular compartments, the rates of synthesis, and the metabolism of albumin are all significantly altered during inflammation and stress.It was reported that the normal transcapillary escape rate for albumin increases by 100% after cardiac surgery.In addition, the transcription rate of albumin messenger ribonucleic acid is decreased in response to inflammation [16][17][18] .Anti-inflammation and immune regulation are also two important physiological roles of albumin [18] .Therefore, hypoalbuminemia could reflect a systemic immune-inflammatory state and further enhance the inflammatory response.A lower albumin level has predicted higher in-hospital mortality in both ATAAD and type B AD [19] .PNI is an effective index that integrates two inflammatory markersserum albumin and lymphocytes.Previous studies reported that PNI was independently associated with all-cause and cardiovascular mortality in patients hospitalized for acute heart failure, coronary artery disease, or infective endocarditis [21,22] .Similar prognostic predictive values have been observed for PNI in patients after cardiac surgery, including CABG or aortic valve replacement [22][23][24] .Recently, several studies revealed its intimate association with ATAAD.Low PNI at admission has been strongly correlated with in-hospital mortality in patients after surgery, especially in hypertensive patients, even after adjusting for other risk factors [10,11] .Though we found that prePNI was lower in patients with delayed extubation, it was not an independent risk factor after multivariate analysis.This discrepancy might be attributed to the different populations, statistical methods, and surgical processes.Furthermore, those studies did not assess the influence of postPNI on prognosis.In this study, we found that low postPNI well predicted poor clinical outcomes after multivariate logistic regression analysis.PostPNI was significantly lower in the groups with the poor clinical outcomes of delayed extubation or 30-day mortality.Inflammation is an important regulator of coagulation and fibrinolytic system activity.Acute inflammation is known to shift the hemostatic balance toward a prothrombotic and antifibrinolytic state, and FIB could also be a driver of local inflammation [25] .An animal study showed that FIB was oxidized at first and proteolyzed three hours later in response to leukocyte-associated inflammation [26] .Changes in coagulation and fibrinolysis are prominent in ATAAD patients due to acute inflammatory response, endothelial injury, formation of false lumen, and thrombosis.A Swedish study described that FIB levels at admission were significantly lower in ATAAD patients than in patients undergoing surgery of the ascending aorta or the aortic root in mild-to-moderate hypothermia [27] .The levels of FIB further decreased after CPB.Low FIB (< 2.17 g/L) at admission was reported to be an independent predictor of in-hospital mortality in patients undergoing ATAAD surgery, especially in patients > 65 years [28] .However, few studies have discussed the influence of postFIB.We found that low postFIB was strongly associated with delayed extubation, reintubation, and 30-day mortality after adjusting for confounders in this study.These results indicate that low postFIB could well predict poor clinical outcomes and might be a promising prognostic marker of ATAAD after surgery.

Table 1 .
Baseline characteristics of acute type A aortic dissection patients by different clinical outcomes.

Table 2 .
Perioperative immune-inflammatory parameters by different clinical outcomes.

Table 3 .
Prognostic parameters screened by univariate and multivariate logistic regression analysis.
BMI=body mass index; CI=confidence interval; CPB=cardiopulmonary bypass; DD=D-dimer; FDP=fibrinogen degradation products; FIB=fibrinogen; OR=odds ratio; PNI=prognostic nutritional index *Pre.stands for preoperative values and Post.stands for postoperative values **Age, gender, BMI, history of diseases, smoking, drinking, and preoperative mulperfusion were adjusted during multivariate analysis

Table 4 .
ROC analysis of postPNI and postFIB by different clinical outcomes.